Immediate and Long-Term Career Goals: Jose U. Scher, MD, has a strong background in clinical immunology and rheumatology, as well as basic and translational research. His overarching career goal is to become an independent academic research scientist working at the interface between rheumatic diseases, immunology, microbiology, and computational analytics in the area of causal discovery methods. To achieve this long-term goal, Dr. Scher plans to extend his research area into the medical sciences through a plan for acquiring 'omics and computational expertise, as well as learning essential skills for upstream and downstream analysis of large datasets. Environment - Key Elements of the Research Career Development Plan: Dr. Scher is currently a junior faculty member in the Department of Medicine, Division of Rheumatology at New York University School of Medicine. Under the guidance of the mentoring team (mentor Dr. Steven B. Abramson; co-mentor Dr. Constantin Aliferis), collaborators (Drs. Martin Blaser, Andrea Neimann, Jonathan Samuels) and advisors, Dr. Scher will enter a rigorous training program consisting of: 1) hands-on research training in advanced computational analytics; 2) formal didactic training via graduate courses in Advanced Causal Pathway Discovery Methods, Computational Studies, Biostatistics, and Clinical Trials Design; 3) contribution to journal clubs and group meetings in the research groups of the mentors, collaborators and advisors; 4) participation in national and international conferences and symposia; and 5) participation in training courses in the responsible conduct of research. Research Project: Psoriatic arthritis (PsA) is a chronic inflammatory disease of unknown etiolology, occurring in about one third of people with psoriasis of the skin (a condition that affects 2-3% of the population). Gut and skin microbiota (the totality of microbes that reside in/on the human body) have long been thought to contribute to inflammatory diseases, and multiple reports in animal models and humans suggest a predominant role in autoimmune and rheumatic disease manifestations. There is strong genetic, clinical and therapy-based evidence that psoriasis, psoriatic arthritis and inflammatory bowel diseases represent examples of the same disease spectrum. Given the long-considered hypothesis that bacterial infection could represent an environmental trigger for PsA development, the application of modern microbiology technologies and causal discovery methods to assess this question could have significant impact on the field. We therefore propose to study the role of intestinal and skin microbiota in PsA utilizing state-of-the-art, culture-independent, DNA sequencing techniques coupled with sophisticated computational analytical tools. Our primary hypotheses are that: 1) characterization of microbes in human intestine/skin will provide insight into disease pathogenesis; and 2) gut/skin microbiota are associated with local and systemic immune responses potentially responsible for (and predictive of) the passage from psoriasis of the skin to PsA. Insights attained may elucidate how microbial communities interact with host intestinal/cutaneous components and provide a rationale for the development of new diagnostic and therapeutic approaches for PsA. Two primary Specific Aims are proposed: Aim 1) To study the role of intestinal microbiota in new-onset Psoriatic Arthritis by: a) characterizing the alterations of skin microbiota community at the onset of PsA; and b) studying the link between intestinal microbiota in PsA patients and the local intestinal immunologic response. Aim 2) To determine the role of skin microbiota in new- onset PsA by: a) investigating whether alterations in the skin microbiota correlate with phenotypic differences in patients with psoriasis of the skin versus PsA patients; and b) studying the association between skin microbiota in PsA patients and the systemic immunologic response. An additional secondary aim, Aim 3, will also be pursued in order to a) expand an established longitudinal database/biorepository for the study of natural history of PsA and b) investigate whether baseline skin and/or gut microbiota can predict development of arthritis/enthesitis. Carefully selected outcomes should permit us to correlate the presence of a specific microorganism or microbiome pattern with changes in immune response, other specific biomarkers, and clinical activity. Relevance: This project is consistent with the goals of the Human Microbiome Project, a major NIH Roadmap initiative, and has the potential to be truly transformative by filling a fundamental knowledge gap regarding the cause of inflammatory arthritis. The results could transform our understanding of the relationships between microbes and humans, and lead to innovative diagnostic tests and future treatments.